GABA receptor subtype antagonists in the nucleus accumbens shell and ventral tegmental area differentially alter feeding responses induced by deprivation, glucoprivation and lipoprivation in rats

Abstract

GABA_A and GABA_B receptor agonists stimulate feeding following microinjection into the nucleus accumbens shell and ventral tegmental area, effects blocked selectively and respectively by GABA_A and GABA_B receptor antagonists. GABA antagonists also differentially alter opioid-induced feeding responses elicited from these sites. Although GABA agonists and antagonists have been shown to modulate feeding elicited by deprivation or glucoprivation, there has been no systematic examination of feeding elicited by homeostatic challenges following GABA antagonists in these sites. Therefore, the present study examined the dose-dependent ability of GABA_A (bicuculline, 75–150 ng) and GABA_B (saclofen, 1.5–3 μg) antagonists administered into the nucleus accumbens shell or ventral tegmental area upon feeding responses elicited by food deprivation (24 h), 2-deoxy-d-glucose-induced glucoprivation (500 mg/kg) or mercaptoacetate-induced lipoprivation (70 mg/kg). A site-specific effect of GABA receptor antagonism was observed for deprivation-induced feeding in that both bicuculline and saclofen administered into the nucleus accumbens shell, but not the ventral tegmental area, produced short-term (1–4 h), but not long-term (24–48 h) effects upon deprivation-induced intake without meaningfully altering body weight recovery. In contrast to the relative inability of GABA receptor antagonism in both sites to alter 2-deoxy-d-glucose-induced intake, mercaptoacetate-induced intake was eliminated by saclofen and significantly reduced by bicuculline in the nucleus accumbens shell and eliminated by both bicuculline and saclofen in the ventral tegmental area. These data reinforce the findings that GABA_A and GABA_B receptors in the nucleus accumbens shell and ventral tegmental area are not only important in the modulation of pharmacologically induced feeding responses, but also participate in differentially mediating the short-term feeding response to food deprivation in the nucleus accumbens shell as well strongly modulating lipoprivic, but not glucoprivic feeding responses in both sites.

Introduction

Site-specific feeding responses can be elicited by direct administration of GABA or its agonists into the ventral tegmental area (VTA: e.g., Arnt and Scheel-Kruger, 1979, Echo et al., 2002, Khaimova et al., 2004, Klitenick and Wirtshafter, 1988), nucleus accumbens (NAC) shell (e.g., Soderpalm and Berridge, 2000, Stratford and Kelley, 1997, Ward et al., 2000, Znamensky et al., 2001), substantia nigra (SN: Redgrave et al., 1984; but see Kelly et al., 1977), median (Klitenick and Wirtshafter, 1989, Wirtshafter et al., 1993) and dorsal (Bendotti et al., 1986, Borsini et al., 1983) raphe nuclei and ventro-medial hypothalamus (VMH: Grandison and Guidotti, 1977, Kelly et al., 1977, Tsujii and Bray, 1991) in free-feeding rats. In contrast, GABA agonists suppress food intake following microinjections into the central nucleus of the amygdala and lateral hypothalamus (LH) (Kelly et al., 1977, Minano et al., 1992). Among these sites, the NAC shell and tegmental area (VTA) have been implicated in the mediation of reward and reinforcement related to appetitive, ingestive, stress-related, aversive and drug-seeking behaviors (e.g., see reviews: Kelley, 1999, Kelley, 2004) traditionally through dopamine mechanisms (e.g., see reviews: Berridge and Robinson, 1998, Salamone, 1994). Although dopamine plays an important role in these processes, other modulatory transmitters, including GABA connections between these nuclei (Van Bockstaele and Pickel, 1995), have been implicated in mediating ingestive responses. Thus, GABA receptor subtype antagonists selectively and specifically reduce feeding induced by GABA receptor subtype agonists in the VTA (Echo et al., 2002) and NAC shell (Stratford and Kelley, 1997, Znamensky et al., 2001). Thus, feeding elicited by the selective GABA_A agonist muscimol is blocked by pretreatment with the GABA_A antagonist bicuculline but not the GABA_B antagonist saclofen in either the NAC shell or the VTA. Correspondingly, feeding elicited by the selective GABA_B agonist baclofen is selectively blocked by pretreatment with the GABA_B antagonist saclofen but not bicuculline in either the NAC shell or the VTA. Region-specific effects in the NAC shell were observed such that muscimol increases feeding, visits to food, place preferences and positive hedonic reactions after administration into the rostral NAC shell and defensive paw-treading and burial behaviors after administration into the caudal NAC shell (Reynolds and Berridge, 2001, Reynolds and Berridge, 2002). Muscimol in the NAC shell activates Fos-like immunoreactivity in the lateral hypothalamus, lateral septum, paraventricular hypothalamus, ventral tegmental area, substantia nigra and nucleus of the solitary tract (Stratford and Kelley, 1999), stimulates intake of both carbohydrates and fats regardless of whether the macronutrients are presented singly or together and increases intake of sucrose, but not water, saccharin or saline (Basso and Kelley, 1999). However, increases in spontaneous intake, but not operant lever-pressing for food, are observed following muscimol, DAMGO or amphetamine administered into the NAC shell (Hanlon et al., 2004). Finally, muscimol administration into the central amygdala reduces GABA_A-agonist-induced feeding elicited from the NAC shell (Baldo et al., 2005).

GABA receptor agonists and antagonists interact with other transmitter systems in modulating feeding responses. Within the hypothalamic paraventricular nucleus (PVN), combined muscimol and NPY microinjections synergize to increase food intake, an effect not observed in senescent rats (Coppola et al., 2005, Pu et al., 1999). NPY Y1 or Y5 receptor antagonists block muscimol-induced feeding elicited from the NAC shell (Stratford and Wirtshafter, 2004). Muscimol infusion into the NAC shell increases c-Fos in orexin-containing neurons in the perifornical area and NPY neurons in the arcuate nucleus, while decreasing c-Fos in cocaine–amphetamine-related transcript- and proopiomelanocortin-containing neurons in the arcuate nucleus (Zheng et al., 2003). Glutamate–GABA interactions in feeding are evident by the facts that feeding elicited by AMPA/kainite antagonists in the NAC shell is blocked by muscimol infusions into the LH (Maldonado-Irizarry et al., 1995) and that muscimol-induced feeding in the NAC shell is blocked by LH administration of D-AP5 (Stratford and Kelley, 1999). GABA receptor subtype antagonists in the NAC shell and VTA also locally modulate opioid-agonist-induced feeding responses. Feeding elicited by the μ opioid agonist DAMGO in the NAC shell was respectively enhanced and reduced by NAC shell pretreatment with GABA_A (bicuculline) and GABA_B (saclofen) antagonists (Znamensky et al., 2001). DAMGO-induced feeding elicited from the VTA was significantly reduced by VTA pretreatment with saclofen in the absence of conditioned aversions and pretreatment with bicuculline in the presence of seizure activity (Echo et al., 2002). In contrast, if either GABA antagonist was administered in one site (e.g., NAC shell) and the opioid agonist was administered into the second site (e.g., VTA), the resultant opioid-mediated orexigenic responses were unaffected, indicating a lack of regional GABA–opioid interactions (Ackerman et al., 2003). Moreover, DAMGO-induced feeding elicited from the NAC shell is blocked by temporary inactivation with high doses of muscimol of the dorsomedial hypothalamus, LH, VTA, nucleus tractus solitarius or amygdala (Will et al., 2003, Will et al., 2004). In turn, opioid receptor subtype antagonists locally modulate feeding responses elicited by GABA receptor agonists within the NAC shell and VTA. Muscimol-induced feeding elicited from the VTA was significantly enhanced by μ or δ antagonists and was significantly reduced by κ antagonists. Baclofen-induced feeding elicited from the VTA was significantly reduced by μ or κ, but not δ antagonists. Muscimol-induced feeding elicited from the NAC was significantly reduced by μ, κ or δ antagonists. Baclofen-induced feeding elicited from the NAC was significantly reduced by κ or δ, but not μ antagonists (Khaimova et al., 2004).

Whereas the role of GABA in modulating pharmacologically induced feeding responses elicited from the NAC shell and VTA has been studied extensively, relatively little is known about GABAergic modulation in the NAC shell or VTA of homeostatically controlled feeding responses. Previous studies demonstrated that systemic pretreatment with either the GABA-transaminase inhibitor ethanolamine-O-sulfate (Olgiati et al., 1980) or the GABA agonist THIP (Blavet et al., 1982) decreased intake in both freely fed and food-deprived rats, whereas systemic picrotoxin or bicuculline failed to alter chlordiazepoxide-induced increases in deprivation-induced intake (Sanger, 1984). Muscimol, but not baclofen, microinjections into the central nucleus of the amygdala decreased deprivation-induced intake that was blocked by bicuculline pretreatment (Minano et al., 1992). Moreover, memories of tasks related to food reward in food-restricted rats were respectively attenuated and enhanced by muscimol and bicuculline treatment in the amygdala (Salinas and McGaugh, 1996). Muscimol administration into the VMH stimulated spontaneous intake in lean, but not genetically obese Zucker rats (Tsujii and Bray, 1991). Whereas GABA_A receptor antagonism with bicuculline in the anterior piriform cortex stimulated intake of an amino acid imbalanced, but not a basal diet, GABA_B receptor antagonism with phaclofen in the anterior piriform cortex stimulated intake of the basal, but not the amino acid imbalanced diet (Truong et al., 2002). Acute glucoprivic feeding responses elicited by either 2-deoxy-d-glucose (2DG) or insulin were abolished by intracisternal administration of ethanolamine-O-sulfate (Nobrega and Coscina, 1982). Furthermore, glucoprivic feeding responses induced by 2DG, 5-thioglucose or insulin were blocked by either systemic or VMH, but not LH microinjections of either picrotoxin or bicuculline (Lenin Kamatchi et al., 1984, Lenin Kamatchi et al., 1986). In contrast, microinjections of bicuculline into the LH enhanced sweetened milk intake (Kelly et al., 1977).

The present study examined the dose-dependent and time-dependent ability of the GABA_A receptor antagonist bicuculline and the GABA_B receptor antagonist saclofen administered into either the NAC shell or the VTA to alter feeding responses induced by 24 h of food deprivation, 2DG or mercaptoacetate (MA). Both the anti-metabolic glucose analogue 2DG (e.g., Wick et al., 1957) and the free fatty acid oxidation inhibitor MA (e.g., Bauche et al., 1981) elicit glucoprivic (e.g., Smith and Epstein, 1969, Smith and Root, 1969) and lipoprivic (e.g., Langhans and Scharrer, 1987, Scharrer and Langhans, 1986) feeding responses respectively.